In recent years, there has been considerable effort to provide systems that are capable of controlled release of drugs in animals, including humans. Some drugs can only be administered to a patient by injection. Controlled release of such drugs has the advantage that the patient does not need to be subjected to multiple injections, but instead only one or a few injections with the controlled release system would suffice.
Some injections into areas of the patient's body are (very) painful and intrinsically increase the risk of infection. Examples of such difficult to dose areas are the eyes, the (synovial) joints, the muscles or the spine. Injection with a drug in a controlled release system will limit the amount of injections needed and will enhance the chance that a patient will continue with the therapy and/or reduce the risk of infection. This will greatly increase the success of the treatment.
Controlled release systems that are very suitable for being injected into such difficult to dose areas are thermogels based on compositions comprising polymers. The polymers have the unique property that at low temperatures they are water soluble, whereas at higher temperatures the polymers become insoluble and form a gel. Preferably, for use as a system that is capable of controlled release, the polymer is soluble in the solvent used at room temperature (e.g. 21° C.) and forms a gel once injected into the body (temperature in the range from 30 to 42° C.).
A gel (or a hydrogel in the context of the present invention) is a network of polymer chains that are hydrophilic and contain a substantial amount of water (for example between 50 and 99% water, preferably between 66 and 85% water). The gel shows no flow in a vial tilt test: when a glass vial which contains the gel is turned upside down, no flow of the gel is observed during 15 seconds observation time.
Such thermogels are known from for example Zentner et al., Biodegradable block copolymers for delivery of proteins and water-insoluble drugs, Journal of Controlled Release 72 (2001), 203-215. In this article, the release of several drugs from BAB-type biodegradable thermal gels (marketed under the name ReGel®) is described. This ReGel® polymer is a water soluble, biodegradable polymer at temperatures below the gel transition temperature (so at the injection temperature) and forms a hydrogel inside the patient once injected. The hydrogel forms a controlled release drug depot and according to the article is capable of stabilizing poorly soluble and sensitive drugs, including proteins.
In this article, an example of a drug that is highly soluble in water is given: the in vitro release of g-CSF in 23% w/w ReGel® is described. However, as can be seen from FIG. 13, the drug is already released for 60% by the ReGel® system in the first two days. Such so-called burst release is not very advantageous for drugs which require a more constant dosage, such as peptides or anti-inflammatory drugs. For such drugs, a more linear release profile is desired and therefore, it is the object of the invention to provide compositions that are very suitable for controlled release of water soluble drugs (by forming a gel) with a decreased burst release, preferably with a linear release profile.
Within the framework of the invention, with ‘water soluble compound’ is meant that the solubility of the compound in water measured at 20° C. and at atmospheric pressure (1 bar) is at least 20 μg/ml. Solubility in water is determined using the method as described in the Pharmaceutical codex, twelfth edition, page 42, hereby included by reference. For example, the solubility may be determined by shaking an excess of the compound to be dissolved with water at 20° C. at atmospheric pressure (1 bar) until an equilibrium is reached. The solution is then filtered to remove the undissolved compound and the concentration of the dissolved compound is determined by liquid chromatography with UV-absorbance using a calibration curve of the dissolved compound.